2. Academic Validation
  3. Design, synthesis and biological evaluation of 4-aminoquinoline derivatives as receptor-interacting protein kinase 2 (RIPK2) inhibitors

Design, synthesis and biological evaluation of 4-aminoquinoline derivatives as receptor-interacting protein kinase 2 (RIPK2) inhibitors

  • J Enzyme Inhib Med Chem. 2023 Dec;38(1):282-293. doi: 10.1080/14756366.2022.2148317.
Tiantian Fan 1 2,  Yinchun Ji 3,  Danqi Chen 1,  Xia Peng 3,  Jing Ai 2 3 4,  Bing Xiong 1 2
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P. R. China.
  • 2 University of Chinese Academy of Sciences, Beijing, P. R. China.
  • 3 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P. R. China.
  • 4 Hangzhou Institute for Advanced Study (UCAS), Hangzhou, P. R. China.
PMID: 36408835 DOI: 10.1080/14756366.2022.2148317
Abstract

Receptor-interacting protein kinase 2 (RIPK2) is an essential protein kinase mediating signal transduction by NOD1 and NOD2, which play an important role in regulating immune signalling. In this study, we designed and synthesised a novel series of 4-aminoquinoline-based derivatives as RIPK2 inhibitors. In vitro, compound 14 exhibited high affinity (IC50 = 5.1 ± 1.6 nM) and excellent selectivity to RIPK2 showing in a dendrogram view of the human kinome phylogenetic tree. Bearing favourable lipophilicity and eligible lipophilic ligand efficiency (LipE), compound 14 was selected to investigate cellular anti-inflammatory effect and was identified as a potent inhibitor to reduce the secretion of MDP-induced TNF-α with a dose-dependent manner. Moreover, compound 14 showed moderate stability in human liver microsome. Given these promising results, compound 14 could serve as a favourable inhibitor of RIPK2 for further physiological and biochemical research so as to be used in therapeutic treatment.

Keywords

NOD; RIPK2 inhibitor; immunity; inflammation.

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